The first project -Genetic Modifiers of Tamoxifen-Related Breast Cancer Risk: NSABP P1G3- was a case/case analysis of 39 SNPs in 19 different genes among 249 women with invasive breast cancer (84 exposed to tamoxifen; 165 placebo). This was a null study by single SNP association and haplotype analysis. However, the constellation of alleles characterizing cases emerging in the presence of tamoxifen (resistant genotypes) was distinct from that in the unexposed (placebo) cases. This published pathway analysis approach generated an allelic signature that has potential as a predictive biomarker of tamoxifen resistance. This project is now complete.Using NCI's PLCO cancer screening trial, we have been investigating the relationship between the Insulin-Like Growth Factor (IGF) Signaling Pathway and Risk of Advanced Colorectal Adenoma, prompted by data suggesting that IGFs may represent potentially modifiable cancer risk factors. We have analyzed 800 participants found to have an advanced colorectal adenoma at the time of baseline screen, and 800 matched non-adenoma subjects. 37 SNPs in 7 IGF-related genes (IGF1, IGF-BP3, ALS, IGF-1R, IGF-BP5, IGF2, GH) were genotyped, and circulating levels of IGF-1, IGF-2 and IGFBP-3 were assayed. The latter documented a 1.7-fold increase in adenoma risk (95% C.I. 1.2-2.5) in highest vs. lowest quartiles of IGF-1, controlled for IGF-2, IGF-BP3 and numerous other covariates. These data have been published. We also confirmed the previously-observed strong relationship between IGF-BP3-01 (rs2854744), and a new association between IGF-BP3-07 (rs6413441) and circulating levels of IGF-BP3 among controls. This study has been expanded by adding additional genotyping data from the DCEG Rare Cancers iSELECT study which, serendipitously, analyzed the same set of DNA samples. These data provide a more comprehensive interrogation of IGF signaling pathway genes: 1,338 advanced colorectal adenoma cases and 1,503 matched controls were studied, and data generated for 570 single nucleotide polymorphisms (SNPs) in 28 IGF pathway genes. Two SNP associations remained statistically significant after a gene-based correction for multiple testing, one in an intron of the oncogene, KRAS, was associated an increased risk of adenoma (OR per allele=1.36, 95% CI =1.13-1.63, P=0.001), and the other in the serine/threonine kinase gene, RPS6KB1, was associated with a reduced risk of adenoma (OR per allele=0.83, 95% CI=0.73-0.95, P=0.006). This project is now complete. We have developed a portfolio of projects evaluating Genetic Risk Factors for Osteogenic Sarcoma [CAS 10375]. Osteogenic sarcoma (OS), the most common malignant primary bone tumor, occurs most commonly during the adolescent growth spurt. As part of a prospective case-control study of OS initiated in 1995 with the NCI and Harvard Dental School, we studied genetic variation in many genes/pathways implicated in the cellular regulation of growth. We identified a small haplotype block that was associated with risk of OS in the IGF2R gene. This genomic region (near exon 16) consists of CpG islands, and functional analysis of the SNPs in this block suggested that a specific SNP associated with OS risk resulted in differential methylation at that SNP site. Because OS is one of the syndrome-defining malignancies in patients with germ-line TP53 mutations (i.e., the Li-Fraumeni Syndrome), we investigated the role of germ-line genetic variants in TP53 as OS risk factors. These data did not indicate a strong link between variation in TP53 and OS risk, although they did provide preliminary evidence of an increased risk of OS associated with TP53 variants IVS2+38 and Pro72Arg. We recently updated the descriptive epidemiology of OS in two separate publications: one based on US data from NCI's SEER program, and the other based on multiple international cancer epidemiology databases. We published a meta-analysis of height and birth weight as OS risk factors. The data confirmed that height is a significant risk factor for OS. The evidence related to birth weight was not definitive. We recently published the first multistage GWAS targeting OS consisting of 941 OS subjects and 3,291 cancer-free adult controls. Two loci achieved genome-wide significance: a locus in the GRM4 gene at 6p21.3 (encoding glutamate receptor metabotropic 4; rs1906953; P = 8.1 10-9) and a locus in the gene desert at 2p25.2 (rs7591996 and rs10208273; P = 1.0 10-8 and 2.9 10-7, respectively). A validation OS cohort has been assembled to confirm our observations. In addition, these two loci are now undergoing fine-mapping/re-sequencing to uncover the biological mechanisms underlying susceptibility to osteosarcoma. We performed a case-case GWAS of osteosarcoma patients with and without metastases at diagnosis which identified novel functional variants in NFIB as associated with metastasis. Our sequence analysis of TP53 in osteosarcoma cases found a higher than expected frequency of germline mutations in individuals with osteosarcoma.We also contributed to a Workshop that brought together key opinion leaders and experts in the metastasis and osteosarcoma communities and which focused on developing therapeutics that target metastatic progression. Finally, we have contributed more than 1,000 BRCA1/2 mutation carriers accrued from three related studies (Etiologic Studies of Hereditary Breast/Ovarian Cancer [HBOC], Pilot Study of Breast MRI in HBOC, and the National Ovarian Cancer Prevention and Early Detection Study) to identify genetic modifiers of BRCA1/2-related breast and ovarian cancer. This project is a collaboration with the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) which has yielded 40 peer-reviewed publications and an additional 8 manuscripts under review, all focused on detecting common, low-penetrance genetic variants which modify the risk of breast and ovarian cancer in the HBOC context. This project is designed to help develop more precise cancer risk stratification models which might permit more accurate cancer risk assessment in women with HBOC. The highest impact publication during the past year has been the massive genotype/phenotype analysis of CIMBA's collection of 20,000 BRCA1 and 12,000 BRCA2 mutation carriers from 55 centers in 33 countries on 6 continents (T Rebbeck et al., JAMA 2015; 313(13):1347-1361) which identified multiple specific regions within each gene that were associated with higher or lower risks of breast or ovarian cancer. This work should form the foundation of being able to counsel patients regarding their cancer risks based on the specific mutation they carry.